DERIVATIVES OF 4a,9b-DIHYDRO-8,9b-DIMETHYLDIBENZOFURAN

ABSTRACT

This disclosure describes derivatives of 4a,9b-dihydro-8,9bdimethyldibenzofuran and of 4a,9b-dihydro-8,9bdimethyldibenzofuran-3(4H)-one useful as intermediates or as analgetic agents.

United States Patent [1 1 Morlock et al.

p 11 3,741,991 {45] June 26, 1973 DERIVATIVES OF 4A,9B-DIHYDRO-8,9B-D1METHYLDIBEN- ZOFURAN [75] Inventors: Elizabeth Benz Morlock, St. Clair Shores, Mich; Jay Donald Albrigllt; Leon Goldman, both of Nanuet,

[73] Assignee: AmericanCyanamid Company,

. Stamford, Conn.

22 Filed: Nov. 23, 1971 [21] Appl.No.: 201,572

Related U.S. Application Data [62] Division of Ser. No. 34,519, May 4, 1970, Pat. No.

" 52 U.S.: Cl. 260/3462 M [51] ,InLCI con 5/34 [58] Field of'Seareh 260/346. 2 M

[56] v References Cited OTHER PUBLICATIONS 571 f Y ABSTRACT This disclosure describes derivatives of 4a,9b-dihydro 8,9b-dimethyldibenzofuran and of 4a,9b-dihydro-8,9bdimethyldibenz ofuran-3(4H)-one useful as inermediates or as analgetic agents.

' 3 Claims, No Drawings DERIVATIVES OF 4A,9B-DIHYDRO-8,QB-DIMETHYLDIBENZOFU- RAN A CROSS REFERENCE TO RELATED APPLICATION This application is a division of our copending application Ser. No. 34,519, filed May 4, 1970 now US. Pat. No. 3,646,060.

.BRIEF SUMMARY OF THE INVENTION i-g (Mali- 7 r/ on;

wherein R is hydrogen, benzoyl or phenylcarbamoyl; R is hydrogen or o-bromobenzoyl; and R is phenyl or anilino.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the present invention are, in general, colorless or yellow crystalline solids with characteristic melting points .and spectral properties. They are soluble in such common organic solvents as lower alkanols, benzene, chloroform, methylene d-ichloride, N,N-dimethylformamide and dimethyl sulfox ide. They are, however, generally insoluble in water.

The novel compounds of the present invention may be readily prepared from 4a,9b-dihydro-8,Qb-dimethyldibenzofuran-3-(4I-I)-one [Pummerer et al., Ber. 55, 3116(1922); Arkley et al., J. Chem. Soc., 2322 (1956)] in accordance with the following reaction scheme:

wherein each conversion is correlated with the corresponding specific example appended hereinafter.

Certain of the novel compounds of the present invention (when R: is ofbromobenzoyl and R is anilino) are active analgetics when measured by the writhing syndrome test for analgetic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med., Vol. 9,'p. 729 1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of l mg./kg. of body weight of phenyl-p-quinone in male Swiss Albinomice weighing 15-25 grams per mouse. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning ofthe trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-p-quinone. The test compound is administered orally to groupsoftwo mice each 30 minutesbefore injection of the phenyl-p-quinone. The total number of writhes exhibited by each group of mice is recorded for a 3 minute period commencing 15 minutes after injection of the phenyl-p-quinone. A compound is consid ered active if it reduces the total number of writhes in.

the following table:

Compound Oral dose mg./kg.

of body weight 4-benzoyl-4a,9b-dihydro-8,9b-di- 200 methyI-Bdibenzofuranyl o-bromobenzoate 3,4,4a,9a-tetrahydro-8,9b-dimethyl- 200 -3-oxo-2-dibenzofurancarboxanilide When mixed with suitable excipients or diluents, the above compounds can be prepared as pills, capsules, tablets, powders, solutions, suspensions, and the like for unit dosage and to simplify administration.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE I Preparation of 1-(4a,9b-dihydro-8,9b-dimethyl-3- dibenzofuranyl)-pyrrolidine To a suspension of 2.00 g. of 4a,9b-dihydro-8,9bdimethyldibenzofuran-3(4H)-one in 50 ml. of methanol. was added 3.4 ml. (2.9 g.) of pyrrolidine and the mixture was heated on a steam bath for minutes. The resulting clear yellow solution was allowed to stand at room temperature for 1 hour. The solvents were removed by evaporation in vacuo to yield a yellow syrupy residue which was redissolved in benzene and evaporated to dryness in vacuo to yield l-(4a.9b-dihydr0- 8,9b-dimethyI-S-dibenzofuranyl)pyrrolidine as a yellow syrup, A f 6.05 and 6.14 ;1..

EXAMPLE [1 Preparation of 4a,9b-dihydro-8,9b-dimethyl-3-(1- pyrrolidinyl)-4-dibenzofura nyl phenyl ketone To a solution of 0.035 mole of l-(4a,9b-dihydro- 8,9b-dimethyl-3-dibenzofuranyl)pyrrolidine, prepared as in Example I, in 200 ml. of benzene was added 4.85 ml. (3.54 g.) of triethylamine and then 4.00 ml. (4.92 g.) of benzoyl chloride. The resulting solution gradually became deep red in color and a gelatinous precipitate separated. The mixture was allowed to stand at room temperature for 20 hours and then was filtered to remove 4.63 g. of triethylamine hydrochloride. Evaporation of the fil-trate in vacuo yielded the crude product as a deep red syrup. One-half of this product was dissolved in benzene and chromatographed on 200 g. of neutral alumina (activity 111). Elution with benzene and evaporation of the eluate yielded 3.27 g. of 4a,9bdihydro-8,9b dimethyl-3-(1-pyrrolidinyl)-4- dibenzofuranyl phenyl ketone as a deep red syrup, A 6.10, 6.19, 6.30 and 6.40 ,u.

EXAMPLE III Preparation of 2benzoyl-4a,9b-dihydro-8,9b-dimethyldibenzofuran-3(4H)-one To a solution of 0.816 g. of 4a,9b-dihydro-8,9bdimethyl-3-(1-pyrrolidinyl)-4-dibenzofuranyl phenyl ketone in 20 ml. of methanol was added 20 ml. of 0.1N hydrochloric acid and then additional methanol was added to dissolve the precipitated oil. After being allowed to stand for 1% hours at room temperature the mixture was filtered to yield 0.515 g. of crude product as a tan solid, m.p. 150l.60C. Recrystallization from absolute ethanol yielded 0.427 g. of 2-benzoyl-4a,9bdihydro-8,9b-dimethyldibenzofuran-3(4H)-one as offwhite needles, m.p. l65l68C., A 5.95, 6.03, 6.11 and 6.24 ,u, A,,,,,, 250 nm (63,150), k 350 nm (61,860);

4 EXAMPLEITIV Preparation dimethyl-4-dibenzofuranyl phenyl ketone To a suspension of 0.156 g. of 2-benzoyl-4a,9bdihydro-8,9b-dimethyldibenzofuran-3(4l-l)-one in methanol and concentrated ammonium hydroxide was added chloroform until the solid was dissolved. The resulting twophase mixture was vigorously stirred for 3 hours. The chloroform layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual yellow gum was triturated with ether andthe resulting suspension was filtered to remove 0.021 g. of starting material. The filtrate was evaporated to dryness under reduced pressure to yield 0.110 g. of 4a,9b'-dihydro-3-hydroxy-8,9bdimethyl-4- dibenzofuranyl phenyl ketone as a yellow solid, M 5.90, 6.06, 6.28 and 6.34 pt.

EXAMPLE V Preparation of 4-benzoyl-4a,9b-dihydro-8,9bdim'ethyl-3-dibenzofuranyl o-bromobenzoate To a solution of 0.00157 mole of 4a,9b-dihydro-3- hydroxy-S,9b-dimethyl-4-dibenzofuranyl phenyl ketone in 10 ml. of pyridine was added 0.345 g. of obromobenzoyl chloride. After 18 hours at room temperature the solution was evaporated under reduced pressure and the semi-solid residue was taken up in ether. The filtered solution was evaporated to dryness under reduced pressure to yield a yellow gum which was dissolved in benzene and chromatographed on 10 g. of alumina (activity III). Evaporation of the benzene eluates and crystallization of the yellow residual gums gave 0.169 g. of 4-benzoyl-4a,9b-dihydro-8,9bdimethyl-3-dibenzofuranyl o-bromobenzoate as colorless crystals, m.p. l18-122C., 5.68, 6.02, 6.20 and 6.27 1.1..

EXAMPLE Vl Preparation of 4a,9b-dihydro-8,9b-dimethyl-3-(lpyrrolidinyl)-4-dibenzofurancarboxanilide To 0.0221 mole of l-(4a,9b-dihydro-8,9b-dimethyl- 3-dibenzofuranyl)pyrrolidine, prepared as in Example I, in m1. of dry benzene was added 2.4 ml. (2.64 g.) of phenyl isocyanate and the solution was allowed to stand at room temperature for 20 hours. The mixture was filtered to yield, after washing with benzene, 2.50 g. of 4a,9b-dihydro-8,9-dimethyl-3-(l-pyrrolidinyl)-4- dibenzofurancarboxanilide as a yellow solid, m.p. l77C., A 6.00, 6.10, 6.22 and 6.39 t.

EXAMPLE VII Preparation of 3,4,4a,9a-tetrahydro-8,9b-dimethyl-3- ox0-2-dibenzofurancarboxanilide A suspension of 1.50 g. of 4a,9b-dihydro-8,9bdimethyl-3-( l-pyrrolidinyl )-4-dibenzofurancarboxanilide in 100 ml. of methanol and 5 ml. of 1N hydrochloric acid was refluxed with stirring for 4 hours. The cooled solution was evaporated to dryness under reduced pressure to yield a gum as residue. Trituration with water yielded a solid which was collected by filtration and recrystallized from ethanol to yield 0.801 g. of 3,4,- 4a,9a-tetrahydro-8,9brdimethyl-3-oxo-2-dibenzofurancarboxanilide as colorless crystals, m.p. l95l97C., 80 mnx H" I We claim 1. A compound of the formula:

wherein R is selected from the group consisting of hydrogen and o-bromobenzoyl.

2. The compound according to claim 1 wherein l1, is hydrogen; 4a,9b-dihydro-3-hydroxy-8,9b-dimethyl-4-' l k l 

2. The compound according to claim 1 wherein R2 is hydrogen; 4a, 9b-dihydro-3-hydroxy-8,9b-dimethyl-4-dibenzofuranyl phenyl ketone.
 3. The compound according to claim 1 wherein R2 is o-bromobenzoyl; 4-benzoyl-4a,9b-dihydro-8,9b-dimethyl-3-dibenzofuranyl o-bromobenzoate. 